ABSTRACT

A Systematic Review of Opioids in the United States

Chase Perkins

Director: Rizalia Klausmeyer, Ph.D

The opioid epidemic is a prevalent concern in American society as overdose deaths continue to increase. Heroin, fentanyl, carfentanil, hydrocodone, and krokadil are five of the most dangerous opioids and they are responsible for a significant portion of the opioid overdose cases. These drugs are all hydrophobic due to their chemical structure, allowing them to easily permeate the blood-brain barrier and agonize the mu- opioid receptor. Fentanyl, one of the synthetic opioids, is one of the most dangerous opioids as it is 80 times more potent than morphine. Carfentanil is among the strongest of the fentanyl analogues. Krokadil is one of the newest opioids and is dangerous because it can easily be synthesized using household chemicals. To access opioids, users and dealers will typically utilize the Dark Web. Prescription opioids can be acquired through Pill Mills, and there has not yet been enough effective government legislation to limit prescription pill outbreaks. While addiction treatment has many promising potential treatments in herbal remedies, brain stimulation, and other medications, the most effective treatment for opioid overdoses is still the Naloxone injection. Overall, the opioid epidemic will continue to worsen due to ongoing synthesis of new synthetic opioids, the emergence of novel drugs such as krokadil, and the continuing ingenuity regarding opioid distribution on the internet.

APPROVED BY DIRECTOR OF HONORS THESIS:

______

Dr. Rizalia Klausmeyer, Department of Chemistry

APPROVED BY THE HONORS PROGRAM:

______

Dr. Andrew Wisely, Interim Director

DATE: ______

A SYSTEMATIC REVIEW OF OPIOIDS IN THE UNITED STATES

A Thesis Submitted to the Faculty of

Baylor University

In Partial Fulfillment of the Requirements for the

Honors Program

By

Chase Perkins

Waco, Texas

May 2021

TABLE OF CONTENTS

Table of Tables and Figures ...... iii

Introduction ...... iv

Chapter One: Physical and Chemical Properties of Various Opioids ...... 1

Chapter Two: Metabolism of Opioids ...... 16

Chapter Three: Methods for Illegal Access of Opioids and Prices ...... 28

Chapter Four: Opioid Treatment and User Demographics ...... 36

Conclusion ...... 46

References ...... 47

ii

TABLE OF TABLES AND FIGURES

Figure 1: Heroin’s chemical structure; Morphine’s Chemical structure ...... 2

Figure 2: Piperidine structure; Fentanyl structure ...... 6

Figure 3: Carfentanil and fentanyl chemical structure ...... 8

Figure 4: The synthesis of carfentanil from 1-benzyl-4-piperidone ...... 9

Figure 5: Hydrocodone’s chemical structure compared to codeine’s ...... 11

Figure 6: Chemical structures of Krokadil, Hydrocodone, and Codeine ...... 13

Figure 7: Fentanyl main metabolic pathway ...... 18

Figure 8: O-demethylation converting hydrocodone to hydromorphone ...... 23

Figure 9: Metabolism of hydrocodone to norhydrocodone by CYP3A4 ...... 24

Figure 10: Metabolism of desomorphine ...... 26

Figure 11: Naloxone chemical structure ...... 36

Figure 12: A study in the relationship between age and heroin use ...... 44

Table 1: Schedule Classification for Opioids ...... 4

Table 2: Street price of various drugs per dose ...... 34

Table 3: A study in treatment with either heroin or methadone ...... 41

iii

INTRODUCTION

The opioid epidemic has worsened in the United States over the last decade as new drugs continue to emerge and there is continuing innovation regarding distribution of the drugs. Fentanyl overdoses have exploded as users are often unaware it is present in the drug they are using. Pharmaceutical companies continue to develop fentanyl analogs, such as carfentanil, and these synthetic opioids are among the most potent drugs known right now. There are also novel drugs, such as krokadil, that can be synthesized using household chemicals and they agonize opioid receptors and are very potent. With technology continuing to advance, it is difficult for law enforcement to keep up with the

Dark Web as it allows opioid distribution that is unregulated. When one market is shut down, another one emerges. Addiction to these drugs is so severe that it requires treatment that is both continuous and intense, making recovery difficult. To understand the opioid epidemic and ultimately help correct it, the drugs need to be studied more and regulation improvement is dire.

iv

CHAPTER ONE

Physical and Chemical Properties of Various Opioids

Heroin

Heroin is one of the most dangerous opioids, as it has a high potential for abuse and is highly addictive. In the United States, heroin is technically labeled as a narcotic analgesic, and it is classified as a Schedule 1 narcotic. All Schedule 1 narcotics in the

United States have no known medical use and have a high abuse potential1

Before the 1970s, heroin was primarily found in the form of a white crystalline solid, which was comprised mostly of diamorphine hydrochloride. Post-1970s, heroin was typically a brownish powder, that was comprised of only 45% diamorphine hydrochloride3. Some of the other scientific names for heroin include diamorphine, acetomorphine, and 3,6- Diacytyl morphine, while the “street” names for heroin include

“black tar”, “smack”, “China White”, and “Harry.”1 Heroin is derived from the opium poppy, which contains compounds known as alkaloids, of which there are approximately

3,000 different forms. These alkaloids are responsible for the physiological effects that heroin induces in a user, and can either be synthetic or naturally occurring4. Morphine is an example of an opioid that is a naturally occurring alkaloid, while heroin is a semi- synthetic alkaloid because it requires an additional synthetic step to convert it from morphine into heroin. Heroin is regarded as a semi-synthetic opioid, because it is derived from morphine, a naturally occurring opioid, but also involves synthetic material. The

1 molecular formula of heroin is C21H25NO5, and its molecular weight is 369.41 g/mol .

There is no data about heroin’s melting point, boiling point, or vapor pressure1. It is rare

1 to have data regarding melting point, boiling point, and vapor pressure of opioids, most likely because it is difficult to garner approval to conduct experiments with these dangerous drugs.

Regarding heroin’s chemical structure, it is fairly non-polar, which is why it is insoluble in water, a polar compound, but it is soluble in organic solvents. Dissolving heroin in its solid form in a weakly acidic solvent is how heroin can be administered intravenously. The basic chemical process to synthesize heroin is to conduct an acetylation reaction on morphine. Figure 1 below shows the chemical structure of both heroin and morphine.

Figure 1: Heroin’s chemical structure; Morphine’s Chemical structure

It can be observed that the chemical structures of heroin and morphine are extremely similar. Instead of the two hydroxyl groups that morphine includes, heroin has acetyl group substituents. To conduct the conversion of morphine to heroin, one needs various chemicals, including acetic anhydride, which provides the acetyl groups, chloroform, alcohol, ether, hydrochloric acid, and sodium carbonate5. After the reaction is complete, the morphine base compound will have been converted to the semi-synthetic heroin

2 compound. These modifications to the morphine base result in a compound that is more lipophilic (non-polar), making it more feasible for the drug to permeate through the blood-brain barrier, making heroin much more potent than morphine. After completing this chemical process, heroin is sent to distributors who will then often cut (dilute) the heroin with various substances, resulting in the multitude of different purities of heroin that can be found on the street. Cutting heroin allows distributors to increase the amount of money they can make from a small amount of pure uncut heroin. Distributors will use substances such as sugar, caffeine, flour, powdered sugar, cornstarch, and even fentanyl1.

Fentanyl is a synthetic opioid even more potent than heroin, so heroin cut with fentanyl is extremely dangerous and has high potential to cause an overdose. Users often do not know the purity of the heroin they are purchasing, which is part of why it is such a dangerous drug, as users might think they have a less potent batch than they actually do, causing them to overdose.

Pain relief was the main function of heroin when it was first created in 1874 as a non-addictive alternate to morphine, as it is an agonist of various pain receptors in the brain3. While heroin was an attempt to be a non-addictive alternate to morphine, this is not what heroin is. When heroin’s metabolites cross the blood-brain barrier, they stimulate various receptors, such as the mu-opioid receptor, but they also stimulate portions of the brain that deal with hormones such as dopamine2. Stimulation of these portions of the brain, in particular the nucleus accumbens, results in tremendous amounts of dopamine being released, causing the user to “catch a buzz.”8 This dopamine release is what causes heroin to be so addictive, as administration initially causes the user to have extremely positive effects. As the user’s body processes the heroin, the positive feeling

3 subsides and negative reinforcement begins (withdrawal symptoms), as the user’s dopamine supply is extremely diminished, leaving the user with the desire to re- administer the drug to return to the positive feeling state. Heroin can either be smoked, administered intravenously, or subcutaneously. Intravenous administration is the most common method of heroin administration7. The solution used in the injection is created using a heating device, often called a cooker, which allows the heroin to dissolve in sterile water. Smoking heroin is often referred to as “Chasing the Dragon.”6

Table 1: Schedule Classification for Opioids

Drug Schedule

Heroin I

Fentanyl II

Carfentanil II

Hydrocodone III

Krokadil I

Fentanyl

Like heroin, fentanyl is classified as a narcotic analgesic, as it is an agonist of primarily the mu-opioid receptor in the brain. Different than heroin, fentanyl is a more potent agonist of these receptors because its molecular structure allows it to penetrate the blood-brain barrier faster and target those respective receptors. Fentanyl’s full chemical name is N-(1-(2-phenethyl)-4-piperidinyl-N-phenyl-propanamide. Street names of fentanyl include “synthetic heroin”, “Drop Dead”, “Flatline”, “Great Bear”, “Tango and

4 Cash”, and “Lollipops.”9 In the United States, Fentanyl is classified as a Schedule II narcotic, as it has limited accepted medical use, but also has high potential for abuse.

Medical use of fentanyl includes prescriptions for cancer patients, as it can be used to treat severe pain. Users have been known to smoke fentanyl, as well as using intravenous, oral, intranasal, and dermal administration routes. Fentanyl is primarily found as a white crystalline powder, but it can also be made into a fentanyl citrate, which can be used in intravenous administration. There is also a yellow powder form of fentanyl, which is referred to as “White Persian”, and this contains 3-methylfentanyl9.

Fentanyl is an extremely dangerous narcotic that is part of the opioid family. One of the reasons that fentanyl is so dangerous is because it is 80 times more potent than morphine9. Fentanyl’s potency is why when experimenting with the drug, forensic scientists such as the ones at Sam Houston University will typically only work with diluted solutions instead of the powdered form. This helps alleviate some of the risk of accidental exposure or overdose. As mentioned in Section 1, heroin is often being cut with fentanyl by distributors. Since fentanyl is so much more potent than heroin, it is exceptionally dangerous when heroin is laced with fentanyl, and the user is not aware.

The danger of fentanyl is shown in CDC data as 67% of opioid-related overdose deaths are attributed to synthetic opioids, such as fentanyl10. Fentanyl use is also continuing to increase across the country, as from 2017-2018, fentanyl use increased by 10%. The CDC also released data that showed that Arizona had a 92.5% increase in fentanyl use, which was by far the largest increase in fentanyl use among the ten states that had an increase10.

Georgia and Ohio were the only two states that showed a decrease in fentanyl use from

5 2017-18. The majorly rural states such as Idaho, North Dakota, South Dakota, and

Alabama consistently showed increased fentanyl usage.

While heroin is a semi-synthetic opioid because it can be derived from morphine, fentanyl is a fully synthetic opioid. Fentanyl is described as a piperidine derivative, meaning it originates from the basic piperidine structure that is shown in Figure 2, with the molecular formula (CH2)5NH. Also shown in Figure 2 is the basic molecular structure of Fentanyl, which has the molecular formula C22H28N2O. Fentanyl’s molecular weight is

336.471 g/mol, which is slightly smaller than heroin’s9. Just like with heroin, there is no data about fentanyl’s boiling point or melting point.

Figure 2: Piperidine structure; Fentanyl structure

Observing the structure of fentanyl, it is non-polar, which allows it to permeate the blood- brain barrier. The more non-polar a drug is, the more easily it can penetrate the lipophilic brood brain barrier and be an agonist of certain receptors. Janssen Pharmaceutical is credited with the original synthesis of Fentanyl by reacting 4-piperidone hydrochloride

6 and phenethyl bromide. This reaction results in N-phenethyl-4-piperidone, or NPP, which can be converted into fentanyl9.

Fentanyl causes euphoria and drowsiness, similar to heroin, but it produces less euphoria than heroin does. The short-term side effects of fentanyl use include nausea, dizziness, and headache, but the potential long-term results of repeated fentanyl use are addiction, tolerance, and overdose9. Withdrawal symptoms are prevalent with fentanyl users, as fentanyl has the same mechanism regarding release of hormones such as dopamine, so after a user “crashes”, they will have a strong desire to re-administer the drug.

Carfentanil

There are many different analogs of fentanyl. These analogs vary in their relative potencies, so some are more potent than others. New analogs are continuously created by manufacturers commercially. When new analogs are created, there is limited legislation regulating the use of these drugs, making it easier for the industry to distribute the drugs.

One of the more potent fentanyl analogs is carfentanil, which is 10,000 times more potent than morphine, and 100 times more potent than fentanyl making carfentanil one of the more dangerous opioids11. Carfentanil is distributed both commercially and illegally, and is classified as a Schedule II narcotic because it has both limited medical use and high abuse potential. Similar to fentanyl, carfentanil is a full agonist of the mu-opioid receptor in the brain causing pain suppression and analgesia, which is why it has limited medical use. On the street, carfentanil is called “elephant tranquilizer” and “C.50.”11 The IUPAC name for carfentanil is Methyl-1-(2-phenylethyl)-4-[phenyl(propanoyl)amino]piperidine-

4-carboxylate, and the chemical formula is C24H30N2O3. Carfentanil’s molar mass is

7 394.515 g/mol. Different than fentanyl and heroin, carfentanil does have data regarding its boiling point and melting point which are 508.1°C at 760 mmHg and 189.5°C, respectively11. Janssen Pharmaceutical company, the group also credited with the synthesis of fentanyl, developed carfentanil in 1974 to be used for analgesia by veterinarians. Carfentanil and fentanyl are very similar in chemical structure. The difference in chemical structure between fentanyl and carfentanil is the addition of a carboxymethyl group on the fourth position of the piperidine ring (Figure 3). This additional carboxymethyl group makes carfentanil more lipophilic, which increases potency because it is easier for the drug to permeate through the blood-brain barrier.

Figure 3 shows the additional carboxymethyl group that carfentanil possesses in comparison to fentanyl.

.

Figure 3: Carfentanil and fentanyl chemical structure

Since carfentanil is so similar to fentanyl in structure, its synthesis process is very

8 similar as both are synthetic opioids. There are multiple different routes of synthesizing carfentanil. One process to synthesize carfentanil includes N-phenehtyl-4-piperadone

(NPP), potassium cyanide (KCN), a mixture of aniline and acid, a mixture of methanol and acid, and propanoyl chloride12. An additional process is shown below in Figure 4, which shows the complicated five step process of synthesizing carfentanil from 1- benzyl-4-piperidone by using reagents such as aniline, KCN, propionyl chloride, HCl,

MeOH, and phenylethyl chloride11.

Figure 4: The synthesis of carfentanil from 1-benzyl-4-piperidone

Carfentanil is typically found as a white crystalline powder, but a user administers

9 carfentanil, they often are unaware they are using carfentanil12. Distributors are

combining carfentanil with heroin to make more money from a smaller batch of pure

heroin, which lowers the purity of the heroin but makes it extremely more potent since

carfentanil is 100 times more potent than fentanyl11. When carfentanil is combined with

heroin, it is usually injected intravenously. The solution that is used in the injection

results from heating the heroin/carfentanil sample as it dissolves in sterile water.

Overdose deaths continue to increase, and the rise of the use of carfentanil in

combination with other opioids is one of the reasons for this.

Hydrocodone

Hydrocodone is another opioid commonly used medically with a high potential for abuse. Similar to fentanyl, hydrocodone belongs to the synthetic opioid family.

Hydrocodone has accepted medical use because when it binds to the mu-opioid receptors, just like the other opioids discussed, it suppresses pain. When hydrocodone is used under medical supervision, it is often used simultaneously with acetaminophen. Hydrocodone used to be routinely abused because it could be found in pharmacy treatments for colds and coughs. Cough syrup containing hydrocodone was first prepared in 194314. To combat this abuse, hydrocodone has been replaced for the most part by dextromethorphan14.

Oral administration of hydrocodone is most frequent and it is known to be 1.5 times more potent than oral morphine15. Compared to the other opioids discussed, hydrocodone is nowhere near as potent (fentanyl and heroin are both more than 50 times more potent than morphine), but it still has a high potential for abuse15. Hydrocodone is a

Schedule II drug because of both its high abuse potential and limited accepted medical

10 use. Before 2014, hydrocodone was a Schedule III narcotic, but upon the growing rise of opioid related deaths attributed to hydrocodone, the DEA reclassified hydrocodone as a

Schedule II drug that removed it as an “over-the counter” option in pharmacies13. Any drug containing hydrocodone was labeled a hydrocodone combination pharmaceutical

(HCPs) and re-classified as Schedule II. These HCP drugs often contained acetaminophen. Studies found that acetaminophen related overdoses (liver failure) were often due to a combination with hydrocodone. The extended release mechanism usually acts over 12 hours, which adds to the danger of the drug because when hydrocodone is combined with other drugs (alcohol, other opioids), it alters the potency and affects metabolism. A user might think that the drug is out of their system, when in fact it is very much present and additional intake could potentially be catastrophic14.

Hydrocodone is also known as dihydrocodeinone, bakadid, and dicodid, its

14 chemical formula is C18H21NO3, and its molar mass is 299.4g/mol . Figure 5 below shows the chemical structure of hydrocodone compared to codeine. Hydrocodone has the exact same chemical formula as codeine, but in the chemical structure, hydrocodone has an oxygen substituent that has been oxidized from an alcohol to a ketone.

Figure 5: Hydrocodone’s chemical structure compared to codeine’s

11

The primary metabolite of hydrocodone, hydromorphone, is particularly dangerous, so any negative effect on metabolism can increase the risk of overdose. This extended release mechanism is extremely different from the other opioids discussed, which have been found to produce effects within minutes of administration and are metabolized relatively quickly. Extended release is a method of administration that is common for opioid addiction treatments, that will sometimes use patches that will release treatment throughout the course of a day or even longer duration. Oral administration as the most common route of administration is also very different from other opioids, who are typically administered intravenously or smoked14.

Krokadil

One of the newest opioids that is contributing to the opioid crisis is krokadil.

Krokadil was first seen in Russia in 2003, but there are concerns that it will soon be prevalent on American streets. In 2011 alone, a study recorded 100,000 krokadil users in

Russia16. Krokadil is also known as desomorphine, and on the street is referred to as the

“zombie drug”, “crocodile”, “Russian Magic”, and “Poor Man’s Heroin.”16 One of the reasons that krokadil is appropriately named is that when a user intravenously administers krokadil, the skin around the injection site will discolor and even appear scaly. Compared to the other opioids discussed, krokadil is more potent than heroin, and approximately ten times stronger than morphine, but not as potent as fentanyl, which is 80 times more potent than morphine. Like heroin, krokadil is a Schedule I narcotic as it has no medical use and has high abuse for potential.

12 17 Krokadil’s chemical formula is C17H21NO2, and its molar mass is 271.35g/mol .

This chemical formula is extremely similar to hydrocodone’s and codeine’s, which are derivatives of each other and have the same chemical formulas, as hydrocodone and codeine both have one additional carbon and one additional oxygen molecule. Figure 6 shows the extreme similarity between the chemical structures of hydrocodone, krokadil, and codeine. The ketone in hydrocodone that was the difference between codeine and hydrocodone has been completely eliminated in krokadil.

a) b) c)

Figure 6: Chemical structures of Krokadil (a), Hydrocodone (b), and Codeine (c)

The extreme similarity between all of these opioids is one of the dangers behind the opioid epidemic. As new opioid analogs are being synthesized both in labs and on the streets, it is difficult for legislation and law enforcement to keep up with the abundance of opioids. With krokadil being so hazardous, easy to synthesize, and cheap, it has the potential of becoming a significant part of the ongoing opioid crisis in America.

In order to synthesize krokadil, suppliers or distributors will use codeine or derivatives of codeine, and the entire process, where codeine is combined with various chemicals, such as gasoline and hydrochloric acid (HCl), can reportedly be completed

13 within 45 minutes16. Concentrated HCl can be extremely corrosive and cause skin burns, and the use of HCl to create the drug is one of the reasons why there is skin deterioration around the administration site. Krokadil has the potential to substantially worsen the opioid crisis because of the ease with which it can be synthesized using common household chemicals. Since the drug is not being synthesized by accomplished chemists, but instead by addicts/suppliers using imprecise recipes, there is a tremendous risk of a

“bad batch”, which could easily cause deaths. Krokadil is more common in low income areas of Russia because it is cheaper than heroin, which also increases the chances that the drug could proliferate tremendously among American low income communities.

Krokadil typically comes in solid form, but has a solubility of approximately

50mg/mL in ethanol (ETOH), dimethyl sulfoxide (DMSO), and dimethyl formamide

(DMF)18. These solvents are prevalent in high school chemistry labs, as well as college labs, and can be easily purchased. These solvents are skin irritants, so in addition to the

HCl that is a commonly found in krokadil, these solvents can contribute to the skin damage around the administration site. Once the solid krokadil is dissolved in these solvents, it can be administered intravenously

After administration, the user will feel effects within 2-3 minutes, and effects will last for several hours after administration. Compared to hydrocodone, krokadil’s mechanism is much different than hydrocodone’s extended release mechanism that will last over a 12 hour period. Krokadil’s mechanism of action is very similar to heroin and fentanyl’s. In the United States, krokadil is classified as a Schedule 1 narcotic, which is the same as heroin, because there is no accepted medical use and the drug has a high potential for abuse16.

14 CHAPTER TWO:

Metabolism of Opioids

Heroin

Heroin and its metabolites are agonists of the mu-opioid receptor. Stimulation of this receptor causes the immune system to be suppressed, as well as the other effects associated with opioid administration. Heroin is quickly metabolized into morphine when it enters the body. Some of these metabolites are more potent than morphine, increasing the danger for potential death. In phase 1 of heroin’s biotransformation, a hydrolysis reaction conducted by cholinesterase transforms heroin into morphine and acetic acid22.

6-acetylmorphine is the intermediate in between heroin and morphine, and this is what makes heroin so much more potent than morphine. 6-acetylmorphine is more hydrophobic, which allows it to permeate through the blood-brain barrier and reach the opioid receptors much easier19. In addition to the opioid receptors, 6-acetylmorphine very easily reaches the nucleus accumbens (Nacc), which is one of the primary sources of dopamine release20. Stimulation of the Nacc is responsible for the “high” that heroin users experience, causing release of dopamine, which is the body’s built-in reward system. After use, a user’s dopamine supply is severely diminished, which is what leads to craving and withdrawal symptoms. This desire by a user to readminister heroin to reach another high is regarded as negative reinforcement, as they are using the drug to stop feeling poorly. Regarding toxicity, 6-acetylmorphine is also more toxic than morphine or heroin, and is usually found as the primary metabolite for heroin overdoses.

The half-life of heroin in humans is found to be 3-8 minutes21. 6-acetylmorphine has a

15 half-life of approximately 15 minutes, and morphine has a half-life of 2-3 hours21. These times show that the time that pure heroin is in the body is relatively short, while morphine can remain present in the body for 5 hours. In addition to 6-acetylmorphine, normorphine is another metabolite of the biotransformation process, but it is considered to be an inactive metabolite.

In the second phase of heroin’s biotransformation, heroin is transformed into a more polar compound via glucuronidation, which allows heroin to be excreted via urine, as these polar compounds are much more hydrophilic19. This glucuronidation process utilizes multiple enzymes, including UDP-glucuronyltransferase, which in turn needs

UDP-glucuronic acid as a co-factor19. The polar compounds that heroin has been transformed into are morphine-3-glucuronoride (M3G) and morphine-6-glucuronide

(M6G). One of the dangers of combining multiple drugs with heroin, such as alcohol, is that the presence of other drugs can interfere with the metabolism process, inhibiting the body’s ability to metabolize heroin and complete proper excretion.

Fentanyl

While the metabolism of heroin is a fairly linear process without much deviation, fentanyl is metabolized in a much more complex manner with multiple possible paths to excretion. Heroin’s structural similarity to morphine leads to its metabolism being so similar to morphine’s. Fentanyl’s structure is not similar to morphine. Instead, fentanyl is a heterocyclic tertiary aliphatic amine with two different variations of phenyl rings that operate as an aromatic amide27. Fentanyl is only metabolized with Phase I biotransformation reactions, with no known Phase II reactions23. The main pathway of

16 metabolism takes place in the liver, where Cytochrome P450 3A4 (CYP3A4) is the enzyme that bio-transforms fentanyl into norfentanyl by inducing oxidative N- dealkylation at the piperidine ring23. After this N-dealkylation, norfentanyl is further put through hydroxylation through the addition of alcohols at various positions making the compound more polar which allows it to be excreted via urine. Figure 7 below shows this pathway that is carried out by CYP3A4.

Figure 7: Fentanyl main metabolic pathway; N-dealkylation followed by 4 possible

hydroxylations

When hydroxylation takes place following N-dealkylation, there are four possible locations for the alcohol to be added. The first and second options are the most common, as it is at the 2 or 3 position on the piperidine ring. Hydroxylation can also take place at the phenyl ring, the amide alkyl chain, or along the linkage between rings. These hydroxylation reactions are essential to the biotransformation of fentanyl into a more hydrophilic molecule, allowing excretion via urine.

17 There are additional metabolic pathways for fentanyl. In one pathway fentanyl undergoes amide hydrolysis, and then hydroxylation where a carboxylic acid is introduced to the molecule, making it hydrophilic and eligible for excretion. The processes that differ from the main N-dealkylation process carried out by CYP3A4 account for less than 1% of fentanyl metabolism23. These alternate processes use a combination of N-dealklyation, hydroxylation, and amide hydrolysis to produce hydroxyfentanyl, hydroxy norfentanyl, and despropionylfentanyl, which are inactive compounds that can be excreted via urine23. Besides the liver, there is an additional metabolic process for fentanyl that takes place in human duodenal microsomes, which are located in the intestines24. In the microsomes, fentanyl is also metabolized to norfentanyl by CYP3A4, which is the same enzyme that is responsible for the hepatic metabolism of fentanyl in the liver. The rate of metabolism of fentanyl in microsomes is approximately half the rate of metabolism in the liver24. Since the liver is also primarily responsible for the metabolism of other drugs, such as alcohol, administration of fentanyl simultaneously with other substances can be extremely dangerous and often lethal, as the metabolic pathways interfere with each other and cannot function with the efficiency and productivity needed.

Numerous minor metabolites result from fentanyl metabolism, and all of these have been detected in various urine samples. Hydroxyproprionyl-fentanyl and hydroxyproprionyl-norfentanyl have both been detected in urine, but these minor metabolites have no data regarding the pharmacological reactions that produce them23.

When fentanyl goes through carboxamide hydrolysis, desproprionyl-fentanyl (4-ANPP) is one of the minor metabolites produced27.

18 Overall from a metabolic point of view, fentanyl is viewed to be less dangerous than morphine because while morphine’s metabolites are known to accumulate in the liver, fentanyl’s have not shown any sign of accumulation. Accumulation of morphine’s metabolites in the liver, namely 6-acetyl-morphine, is linked to severe liver damage.

Fentanyl’s metabolites have been shown to have a higher concentration in saliva than in plasma, which signals ease of transport of fentanyl metabolites, which prevents the metabolites from accumulating in the liver and leading to severe liver damage27.

Regarding kinetics, the half-life of fentanyl is 8-10 hours26. Within 72 hours, approximately 75% of fentanyl has been excreted via urine (depending on dosage), and less than 7% of the fentanyl that is excreted is intact, with the majority being metabolites.

A small amount of fentanyl is excreted via feces, which is the fentanyl metabolized in the microsomes in the intestine. This amount of fentanyl is less than 9% of the original fentanyl, where less than 1% of the fentanyl that is excreted is unchanged23. In the plasma, fentanyl is removed at a rate of .5L/hr/kg. There is no known data about the

LD50 for humans and fentanyl, but for rats and mice, the LD50 was found to be 18mg/kg and 2.91mg/kg respectively25.

Carfentanil

Carfentanil is one of the most potent analogs of fentanyl. Its potency is caused by the methylation at the 4-position on the piperidine ring. This makes the molecule more hydrophobic than fentanyl and other opioids, such as morphine, henceforth allowing it to permeate the blood-brain barrier with ease. Carfentanil is 100 (Sa times more potent than fentanyl and 10,000 times more potent than morphine27. There has not been any human

19 experimentation with carfentanil. The only metabolites that have been detected are all associated with carfentanil fatal overdoses, showing the danger associated with the drug.

The main evidence of carfentanil metabolites comes from the Moscow Hostage Crisis in

2002. On October 26, 2002, Chechen rebels stormed the Moscow Theater and held 800 people hostage for 57 hours28. In a final attempt to defeat the rebels, the Russian Special

Forces released an aerosol mixture at 5:00am containing carfentanil, killing 125 of the hostages. Survivors mentioned a white aerosol emerging from the balcony. The hostages all showed symptoms of opioid overdose, and some of them were able to be saved via naloxone treatment, which is the primary method of treating opioid overdose. Russian government initially claimed that the aerosol mixture was fentanyl and halothane gas, but this mixture is not potent enough for this many deaths28. Carfentanil was determined to be present in the attack after norcarfentanil was found on both the clothing of two survivors and the urine of a separate 56-year-old man. This urine sample was the only one provided to England scientists in 2012 who performed further analysis of carfentanil and its metabolites28. The other opioid present in the mixture was remifentanil, another analogue of fentanyl. Norcarfentanil is a known metabolite of both carfentanil and remifentanil. As norcarfentanil is the main metabolite of carfentanil and remifentanil, it is often difficult to determine which fentanyl analogue was administered when norcarfentanil is the sole metabolite recovered. Norcarfentanil arises as a metabolite from the N-dealkylation reaction that is the main route of carfentanil metabolism27. This process is extremely similar to the main metabolic pathway of fentanyl, which metabolizes into norfentanyl via a N-dealkylation reaction. In total, 11 Phase I and one

Phase II metabolites have been detected for carfentanil.27 The phase II metabolite was a

20 glucuronide, which signals glucuronidation. This glucuronide is the least common of the

12 metabolites27. Glucuronidation’s presence is similar to heroin metabolism, which includes glucuronidation in its Phase II metabolic breakdown. Carfentanil’s Phase II metabolism differs from fentanyl because there are no known Phase II fentanyl metabolites. In addition to N-dealkylation, there was evidence of ester hydrolysis, hydroxylation, N-oxide formation reactions in Phase I carfentanil metabolism27. In addition to N-dealkylation, hydroxylation of the piperidine ring also proved to be one of the more significant metabolic pathways for carfentanil. Like fentanyl, carfentanil is metabolized by Cytochrome P450 enzymes in the liver27.

There is available kinetic data regarding carfentanil metabolism. The half-life of carfentanil is 7.8 minutes, which is extremely shorter than the half-life of fentanyl (7 hours)24. Although the half-life of carfentanil is substantially shorter than fentanyl, both remain in the body for a similar period of time. Carfentanil showed no variation in intensity peaks during a 6-hour span. The clearance estimation for carfentanil is

16.2mL/min per kg of weight24. This data all comes from human hepatocyte testing, which is different from standard human testing. In order to gather more reliable data about carfentanil kinetics and metabolism, human testing is required. However there is a small chance for permission to be granted due to the danger of death present in such study.

Hydrocodone

Metabolism of hydrocodone is of utmost importance because of the drug’s use in the medical field. Hydrocodone has been the most commonly used prescription drug

21 since 2004 in the United States, and it also is very often abused. While hydrocodone has an accepted medical use due to its ability to suppress pain through its mu-opioid receptor activity, there are numerous cases of poisonings related to hydrocodone use. These poisonings can be linked back to the metabolites of hydrocodone. Like most opioids, hydrocodone is metabolized by cytochrome P450 (CYP2D6) in its phase 1 metabolism23.

Hydromorphone is the main active metabolite of this Phase I reaction. Figure 8, below, shows the conversion of hydrocodone to hydromorphone by the enzyme CYP2D6.

Figure 8: O-demethylation by CYP 2D6 converting hydrocodone to hydromorphone

As evidence in Figure 8 above, the overall reaction is O-demethylation where the methyl group is removed from the oxygen substituent of the aromatic ring. In the metabolism of hydrocodone, only about 5-6% of the original hydrocodone is metabolized into hydromorphone. Hydrocodone is also a metabolite of the metabolism of codeine, which is another opioid that has pharmaceutical applications. In addition to hydromorphone, norhydrocodone, dihydrocodeine, isodihydrocodeine, dihydromorphone, and isodihydromorphone are additional metabolites of hydrocodone31. Hydromorphone is the sole pharmaceutically active metabolite of this group31. Norhydrocodone is known as the main inactive metabolite of hydrocodone metabolism, and it results from CYP3A4 being

22 the enzyme involved in the metabolic pathway by performing N-demethylation. This reaction is shown in figure 9 below.

Figure 9: Metabolism of hydrocodone to norhydrocodone by CYP3A4

Norhydrocodone is the most abundant metabolite of hydrocodone, which is important to consider since it is inactive. Issues with hydrocodone metabolism therefore can result in hydromorphone present in higher concentration, which presents a poisoning risk because hydromorphone is 4-6 times more potent than hydrocodone31. Hydromorphone is 5-8 times more potent than morphine31. Combination of hydrocodone with other drugs, such as alcohol, can result in metabolic interference and a potential shift in the abundance of active/inactive metabolites. Interestingly, there is a relationship between ethnicity and metabolism of hydrocodone. Approximately 7% of Caucasians have been found to be poor metabolizers (PM) of hydrocodone29. Hydrocodone itself has no known Phase II metabolic pathway, which is consistent with most opioids.

Regarding lethal cases of hydrocodone use, the average hydrocodone concentration in overdoses is 0.47mg/mL30. The average hydrocodone concentration cases where the drug played a role in death but it was not the main cause of death is

23 0.15mg/mL. In DUI situations, the average hydrocodone concentration is 0.09mg/mL30.

Hydrocodone has been shown to appear in bloodand oral fluid samples within 15-30 minutes after oral administration32. Peak concentrations of metabolites appear 3-9 hours after administration. Studies have shown that hydrocodone can be detected in oral fluid for up to 50 hours after administration, but cannot be detected in blood 24 hours post- administration. The half-life for hydrocodone in oral fluid is 4.4 hours, and the half-life in blood is 4.5 hours32. In a typical prescribed dose of hydrocodone, the tablet contains

10mg of hydrocodone bitartrate and 325mg of acetaminophen32. The often presence of acetaminophen in hydrocodone prescriptions is important to know when dealing with hydrocodone metabolism because alcohol and other drugs can interfere with metabolism of acetaminophen resulting in liver problems.

Krokadil

Desomorphine, or krokadil, is a semi-synthetic opioid that is used as a substitute for heroin. Compared to morphine, krokadil is ten times more potent and affects the user at a faster rate34. Krokadil lacks an alcohol group that is present in morphine, which results in the drug being more lipophilic and more potent as it can easily permeate the blood-brain barrier. It is also excreted from the body at a faster rate than morphine.

There is not much available data regarding the metabolism of krokadil because there have been very few studies performed due to the recent discovery of the drug.

Desomorphine has rarely been found confirmed to be the cause of death in users because its metabolites have been difficult to identify in blood or urine samples. In 2013, the DEA reported only two cases of desomorphine being linked definitively to the cause of death.

24 There is evidence of both phase I and phase II metabolic pathways for krokadil. In the phase I metabolic pathway, there are seven cytochrome P450 (CYP) enzymes that are involved to produce nine different metabolite intermediates33. The enzymes involved are rCYP2B6, rCYP2C8, rCYP2C9, rCYP2C18, rCYP2C19, rCYP2D6 and rCYP3A4, and the metabolites that result are nordesomorphine, desomorphine-N-oxide, two norhydroxydesomorphine isomers, and five isomers that are hydroxylated33. Phase II metabolism of these metabolites involves glucuronidation by UDP-glucuronyltransferase

(UGT) enzymes to create desomorphine-glucuronide. Desomorphine-glucuronide can be excreted via urine. Figure 10, below, shows the two metabolic pathways for krokadil that involve Phase II glucuronidation.

Figure 10: Metabolism of desomorphine to Nor-glucuronide desomorphine (top) and N-

oxide glucuronide desomorphine (bottom)

These two reactions are the only desomorphine metabolic pathways that include Phase II reactions. The remaining seven metabolic pathways include five hydroxylations, a

25 sulfation, and a pathway that goes directly to a glucuronide. The five hydroxy isomers are all created via hydroxylation at various carbons around the molecule. The sulfation occurs at the alcohol substituent of desomorphine. Phase II metabolism only proceeds for desomorphine when the Phase I metabolism results in Nordesomorphine or N-oxide desomorphine. If these two Phase I metabolites are created, glucuronidation takes place to create glucuronide compounds that can be excreted via urine. If Phase I metabolism does not lead to the compounds that prompt glucuronidation, there is an additional pathway in phase I that includes the direct conversion of desomorphine into desomorphine glucuronide. This involves a glucose group attaching to desomorphine’s alcohol substituent34. With so many pathways involved in the metabolism of krokadil, and them all involving cytochrome P450 enzymes, it is extremely dangerous when users administer other drugs simultaneously with krokadil, such as alcohol. CYP enzymes are involved in the metabolism of these other drugs, which will interfere with the ability for these CYP enzymes to metabolize krokadil. This is similar to other opioids, which is why it is common to see other drugs in addition to opioids present in the system of users who overdose.

When krokadil is administered intravenously, its effect is noticed with in 15-30 seconds, which is extremely quick34. Subcutaneous administration results in effects within 3-5 minutes34. There is not a lot of available data regarding pharmacokinetics of krokadil’s half-life. The effects of krokadil lasts approximately an hour and a half. This is much shorter than heroin’s span of effect, which is 4-8 hours. The withdrawal symptoms for krokadil and heroin are similarly both a month in length34

26 CHAPTER THREE

Methods for Illegal Access of Opioids and Prices

Crypto-markets

As mentioned in Chapter 1, opioids are derived from opium as the base ingredient. While Afghanistan is the main producer of opium, which results in 90% of heroin being produced there, synthetic opioids can be created in America. As of 2019, it was surprisingly easy to mail opioids. President Trump made it one of his priorities to cut down on the amount of drugs that were being mailed using the U.S. Postal system35.

Fentanyl and its many analogs are sold most commonly on the internet36. There are many different systems on the internet, and every time law enforcement shuts one down, it seems another one appears. With so many people with advanced computer skills, there is more innovation with online drug distribution than ever. To access these online networks, users and sellers utilize the Dark Web. The Dark Web includes numerous different locations to buy illegal merchandise, including but not limited to drugs, organs, and credit cards. In order to access the Dark Web, one must utilize a special browser as it is inaccessible from the traditional search engines. These special browsers include Tor, which bounces your connection around various proxy servers which hides your activity as your IP address is unidentifiable36.

In 2013, the FBI and DEA had one of their biggest successes regarding shutting down a branch of online drug distribution when they busted the “Silk Road.”37 The

27 name “Silk Road” can be attributed to Chinese history, as the Silk Road was an ancient trade route in China. In 2013, 144,336 Bitcoins were seized from Ross

William Umbricht, who had several aliases such as “Dread Pirate Roberts”, “DPR”, and “Silk Road.”37 Umbricht ran a website on the Dark Web that allowed users to sell and purchase drugs and have them shipped to an address. These Bitcoins that were seized amounted to approximately $33.6 million dollars. It is estimated that Umbricht owned and operated Silk Road from 2011-2013. The types of drugs that were sold on the silk road included opioids as well as cocaine and amphetamines37.

After Silk Road, there was a sequel that appeared on the Dark Web: Silk Road 2.

In 2014, the FBI was able to shut down Silk Road 238. The operation that took down

Silk Road 2 was referred to as “Operation Onymous.”38 Silk Road 2 was run by

Blake Benthall (26), who worked out of San Francisco. Benthall utilized the alias,

“Defcon”, when conducting his illegal business. While in operation, it is estimated that Silk Road 2 made $8 million a month and sold hundreds of kilograms of drugs across the world38. The danger of these Dark Web sites is that they are not solely confined to the United States. Any single one of these sites could distribute to any location in the world, and it is extremely arduous to track the activity due to the ingenious use of servers.

The most current Dark Net operation in an attempt to shut down sites occurred from March-April 201839. This operation utilized a crawler technique, which was specifically designed using sophisticated technology to overcome the security measures of the two target markets, Agora and Dream Market. In these two months,

72,751 ads were discovered, 10,712 of which could be linked to opioid purchase and

28 distribution40. Around 6,976 of these ads were on Dream Market, while 3,736 were

on Agora. Fentanyl and its analogues could be specifically linked to 1,200 of the

opioid advertisements, where 866 were fentanyl and 334 its analogues40. These

numbers were concerning, as it showed an increase in opioid advertisements since

previous observation in 2015. In 2015, there were only 186 fentanyl based

advertisements on Agora40. This increase in opioid sales on these sites can be

attributed to an increase in technological innovation, which in turn results in more

people with the ability to avoid law enforcement and conduct illegal business. As

technology only continues to advance, it is reasonable to assume there are more

opioid advertisements on the Dark Web than ever before.

Illegal Prescriptions

As prescriptions of opioids continued to surge over the last couple of decades, this has been directly linked to the surge in opioid related overdoses. In 2014, there were an estimated 4.7 million Americans using these opioid painkillers and it was estimated that

7% of people who are prescribed these opioids succumb to addiction42. Federal agencies continue to work to shut down these illegitimate clinics in order to cut down on the number of prescribed opioids on the streets. In 2017, it was estimated that half of the overdose deaths related to opioids were due to prescription opioids. From 1991-2011, as the number of opioid prescriptions tripled from 76 million to 219 million, the number of opioid related deaths also tripled42. These prescribed opioids were distributed in various ways. One way was through pain clinics that only serve to sell prescription opioids in order to make a profit. This type of clinic is referred to as a “Pill Mill.”43 These clinics

29 are typically identified by several factors including only accepting cash, not conducting physical exams of patients, quick entry/exit, and medicine is only given in pill form43. In

2003, the DEA arrested Dr. Paul Volkman who was linked to illegal distribution of prescription opioids in West Virginia, Ohio, and Kentucky41. Volkman’s clinics used the typical Pill Mill methods of only accepting cash and not conducting physical examinations of patients. In 2004 alone, Dr. Volkman prescribed the most hydrocodone pills in the whole country. Volkman distributed 457,100 hydrocodone pills in the year, which was 100,000 more than the next largest supplier41. Ohio is one of the most concerning states in the country in regards to opioid distribution. In Scioto County, Ohio, there were 776,163,404 legally dispensed opioids in 2014, which is equivalent to 67 pills per county resident41. This statistic only includes legally dispensed opioids, so the overall number of pills distributed is considerably higher. This large amount of opioid distribution in the state is directly linked to Ohio having the most opioid overdoses in the country41. In 2012, the DEA shut down numerous of these clinics in southern Florida, where they called the operation “Operation Pill Street Blues”, and arrested 12 individuals45. In total, seven clinics and seven doctors were taken down as a result of the operation. Interestingly, two firemen were also among the people arrested45. The opioids that are distributed from these clinics include a hydrocodone/acetaminophen combination drug known as the brand “Norco.” In January 2020, Egisto Salerno was arrested by the

DEA in San Diego for illegal distribution of hydrocodone from a Pill Mill44. Salerno is estimated to have distributed 78,544 hydrocodone pills. He had a legitimate medical license which helped in his illegal distribution from November 2014- February 2018. The other six individuals who were arrested in connection with this San Diego Pill Mill are

30 still awaiting prosecution44. These Pill Mills are prevalent all across the country and are a central part of the prescription opioid epidemic.

Regarding politics, there have been several attempts to mitigate the opioid crisis through the passage of various legislation. States continue to implement legislation to specifically address monitoring of opioid prescriptions. In 2017 in North Carolina, they passed the Strengthen Opioid Misuse Prevention (STOP) Act46. This act applied to

Schedule II and III narcotics, which includes fentanyl, carfentanil, and hydrocodone, but not heroin or krokadil. The STOP Act required prescription of these Schedule II and III drugs to be conducted under increased supervision. The patient must be re-evaluated every 90 days to determine if they need continued medication46. In 2018, the STOP act was amended to more explicitly address opioid prescriptions for acute pain, which is described as any injury that needs three months or less of treatment46. For acute injuries the supervised physician cannot initially supply more than five days’ worth of opioids for treatment upon first visit. If the prescription opioid treatment is for post-surgery pain, the drug supply can be for no more than seven days. This legislation only applies to opioids that are being given to patients who are no longer staying in the hospital, nursing home, or any other supervised medical facility. In 2020, the STOP Act was again amended to address fraudulent written prescriptions by requiring all prescriptions of these drugs to be electronic46.

States have the ability to institute these prescription drug monitoring programs

(PDMPs), which are typically overseen by federal agencies such as the DEA and FDA51.

These PDMPs are online databases containing information about prescription drugs. Each state addresses PDMPs differently. For example, Missouri was initially against the use of

31 PDMPs, but they have since passed legislation to implement them51. Besides PDMPs, there are prescription limits, tamper-resistant prescriptions, patient ID mandates, and regulations involving clinics and how many opioids doctors can purchase51. States also are continuing to try to increase the amount of education that is required of medical professionals in order to prescribe opioids, such as requiring certain permits or specific education courses related to opioids.

There has also been Federal legislation related to the sale of opioids, such as the 1914

Harrison Act which made heroin illegal, but there still lacks substantial federal legislation dealing with prescription opioids, specifically47. The most substantial federal legislation regarding opioids was the 1970 Comprehensive Drug Abuse Prevention Act, which classified heroin as a Schedule I drug47. Federally backed organizations, such as the FDA and DEA, are responsible for dealing with the prescription opioid epidemic. The FDA works currently to educate medical professionals about the dangers associated with prescription drugs, as well as working to test various opioid addiction treatments. The

DEA is the federal agency with the most power when it comes to the federal government controlling narcotics. This is the agency responsible for investigating and shutting down

Pill Mills as well as other sources of illegal prescription drugs.

Legally, there has been an increase in judiciary action against pharmaceutical companies that have been linked to the opioid crisis. On October 21, 2020, Purdue

Pharma, run by the Sackler family, pled guilty to three federal charges associated with illegal activities involving prescription opioids48. Purdue Pharma has been regarded as the main company responsible for the prescription opioid epidemic since the 1990s. In 2007,

Purdue Pharma had its first encounter with illegal opioid distribution when it was charged

32 with misbranding Oxycontin. While two of the charges were associated with fraud and kickbacks, the third charge specifically dealt with the sale of opioids to doctors known for utilizing illegal prescriptions48. Purdue Pharma was hit with a $8.3 billion penalty that was to help compensate victims48. Hopefully, this case will lead to an increase in legal action taken against pharmaceutical companies responsible for opioid misuse. If enough legal action is taken, it could help to alleviate the prescription drug aspect of the opioid crisis.

Prices of Illegal Opioids

Users addicted to opioids will often find themselves spending large amounts of money every day in order to sustain their addiction and ward off withdrawal symptoms.

Dealers take advantage of this because they know that addicts will pay any amount of money in order to acquire the drug. Table 2 shows the street price of heroin compared to other drugs.

Table 2: Street price of various drugs per dose50

Drug Average Price Length of Dose

Marijuana $15-20 per gram 6 hours

Cocaine $100-200 per gram 30 minutes

Heroin $15-20 per dose 2-6 hours

Psilocybin (Mushrooms) $20-25 4-6 hours

LSD (acid) $5-20 per hit 12-24 hours

MDMA (Ecstasy) $15-25 per dose 3-6 hours

Methamphetamine $20/dose; $80/gram 6-24 hours

33 As evidenced in the table, most of these drugs are approximately the same price per dose

($15-20), which the exception of cocaine. While the price of heroin per dose is fairly consistent, users will spend upwards of $200 per day because the drug wears off fairly quickly and withdrawal symptoms set in quickly50. Cocaine addiction can be as expensive as heroin, as heavy users will spend approximately $120 per day50. As illegal narcotics are not a regulated business, the prices of these drugs can vary by demographic because dealers know they can get more money in certain areas.

Prescription opioids are more expensive than other prescription drugs on the streets. Sedative and hypnotic pills, such as Xanax and Valium, will typically have a maximum price of $1.50 per tablet49. These pills are usually sold in bulk. The dealers make a substantial profit on each sale, as pharmacies sell these drugs for around $0.10 per pill49. Compared to other prescription narcotics, such as Demerol and Percocet, opioids are much more expensive. MS Contin, which is a strong opioid prescription medicine that alleviates pain, ranges from $30 - 75 per pill depending on the dose49. The doses of these pills range from 15mg to 200mg49. The average price of these prescription opioids ranges from $20 – 6049. Pharmacies sell these prescription opioids for $0.64 -

4.90 per pill49. Compared to sedative and hypnotic prescription medication, dealers make a larger profit selling prescription opioids. Dealers are taking advantage of the severe addiction that users have to make more money.

34 CHAPTER FOUR

Opioid Treatment and User Demographics

Opioid Overdose Treatment

As opioid overdose related deaths continue to plague the world, there is a necessity for a treatment for overdose victims. In 2017 it was estimated that opioid overdoses were responsible more than 47,000 deaths in the United States52. The numbers have only increased since 2017. Currently, Naloxone® is accepted as the safest and most effective treatment for opioid overdose. Naloxone was first synthesized in the 1961 by Drs. Jack

Fishman and Mozes Lewenstein, and it was approved for opioid overdose treatment via intravenous administration in 1971 by the FDA54. Naloxone is a mu-receptor antagonist, which is the same receptor that opioids target. Naloxone’s chemical formula is

53 C19H21NO4, and its molecular weight is 327.4 g/mol . Figure 11, below, shows the chemical structure of naloxone.

Figure 11: Naloxone chemical structure

35 Naloxone’s structure is extremely similar to morphine. Like morphine and other opioids, Naloxone is non-polar and hydrophobic, allowing it to easily permeate the blood-brain barrier. Unlike opioids, Naloxone is an antagonist of the mu-opioid receptor while opioids are an agonist of this receptor53. While opioids cause pain-relief, euphoria, and sedation when they reach the mu-opioid receptor, naloxone reverses the effects because it competitively inhibits opioids and prevents them from agonizing the receptor53.

Administration routes for naloxone are another topic of importance. The original method of administration, intravenous injection, has hazards that led to studies to find alternative methods of administration. Injection administration creates concerns of both blood-borne illnesses, such as HIV and hepatitis C, and injuries related to improper use of needles57. This method of injection needs ample training in order to be administered properly, which is why new delivery methods were investigated. There are currently alternative administration methods including intramuscular (IM) and subcutaneous (S/C) administration57. IM and S/C are typically able to reverse an overdose within 3-7 minutes, while intravenous administration is effective within 2 minutes57. Inhalation has been viewed as an unsuccessful method of administration since subjects are often not breathing. In 2015, the FDA approved Narcan Nasal Spray as an alternative route of naloxone administration, but it is still not as effective as intravenous administration57.

With this information, there needs to be continued study to find alternative administration routes because administration via injection continues to be the most effective, although it carries the most risk.

36 After intravenous administration, naloxone is metabolized to naloxone-3- glucuronide as well as other metabolites that are products of N-dealkylation or reduction56. Around 60-65% of naloxone is converted into these metabolites before it is excreted via kidney56. The half-life of naloxone is 60 minutes. Its ability to permeate the blood-brain barrier is akin to fentanyl, one of the most potent opioids, as naloxone can equilibrate the blood-brain barrier in 6.5 minutes56. The amount of naloxone needed will depend on the opioid taken by the user. For morphine overdoses, a 1.55ug/kg naloxone concentration is required to reduce the effect of a 12mg sample of morphine in half56.

Fentanyl and heroin overdoses require a higher naloxone concentration as these drugs are more potent than morphine.

In 1996, it was first proposed for naloxone to be released to patients or homes who were viewed as high risk for opioid overdose. This naloxone method of treatment is referred to as take-home-naloxone (THN). Also in 1996, the Chicago Recovery Alliance

(CRA) became the first organization in the United States to distribute THN to high-risk individuals. San Francisco Needle Exchange began distributing THN to juveniles who were involved with opioids in 1999. Federal organizations continue to meet regarding using THN consistently to help limit opioid overdose deaths. In April 2012, the CDC and

FDA met to discuss naloxone treatment for opioid overdoses. THN puts responsibility on the households or companions of the individual who is at high-risk for opioid overdose.

There are programs established for educating these people who are deemed responsible for handling THN and these have shown to be successful. Around 89% of police officers who have undergone these naloxone training programs are confident in their ability to distribute naloxone to victims55.

37 Distribution of naloxone across the country has been successfully improved.

Between 2010-2014, the number of locations that provide naloxone tripled from 188 to

64455. The number of naloxone kits distributed to individuals also tripled from 53,032 to

152,28355. There was also a 94% increase in states with at least one naloxone distribution site. In this same time, the success of naloxone injections also improved. From 2010-

2014, the number of reported reversed opioid overdoses increased by 2.5 times from

10,171 to 26,48355. In 2018, a study was conducted in San Francisco monitoring naloxone use to reverse opioid overdoses. The study found that 89% of the 399 overdose cases were successful in their attempt to use naloxone to reverse the overdose55.

One of the slight risks involved with naloxone administration is cardiovascular issues. There have been reports of pulmonary edema in patients after administration, but pulmonary edema is in itself a common side-effect of opioid overdose56. When naloxone is administered, it increases heart rate, blood pressure, and epinephrine and norepinephrine concentrations. If the concentration of these hormones is too high, it can lead to strokes. The relative dosage of naloxone has been linked to these medical side effects, so it is recommended that naloxone be administered in divided doses. However, there is not yet an exact recommended dosage amount. There have been inconsistent results with various dosage amounts ranging from 0.1mg-0.4mg56. These reported side- effects of naloxone administration are why the person administering the naloxone must be knowledgeable about what they are doing. Experience with intravenous administration limits the possibility of needle related injury or illness. There needs to be further study to find overdose reversal methods that can be performed with limited medical experience and without risk to the subject. While there is slight risk involved with naloxone use,

38 there is no other option in the event of an opioid overdose. The risk of naloxone related medical issues is insignificant compared to the risk of death related to opioid overdose.

Addiction Treatment

Opioid addiction requires intense treatment in order to not only subside withdrawal symptoms but to also prevent relapse. The withdrawal symptoms that arise after opioid use originate from a portion of the brain called the locus coeruleus.

Withdrawal symptoms are monitored by clinics using a system called the Clinical Opioid

Withdrawal Scale (COWS)58. This scale rates withdrawal symptoms with a range 0-47, with intensity of symptoms increasing as the number increases58. In order to stop intense withdrawal symptoms such as nausea, sweating, and shakes, medications are used that target the same receptors as opioids. Methadone and buprenorphine are two drugs that are used to help treat withdrawal symptoms. Methadone is a full mu-receptor agonist, while buprenorphine is a partial mu-agonist, similar to naloxone59. Injecting naltrexone is another method of treating addiction, as naltrexone is not an agonist of any heroin receptors, but it uses competitive inhibition to block the effects of withdrawal. Naltrexone is a better alternative treatment since it is administered under supervision, so there is a decreased risk of diversion of the drug59. One of the problems with treating addiction with methadone and buprenorphine is that the drugs can be diverted and sold on the streets. Repeated use of methadone and buprenorphine can also lead to tolerance so that one might need an increased dose of the drug to get the same effect, while naltrexone does not have a risk of the patient acquiring a tolerance.

39 There is also data from study regarding using supervised administration of heroin to treat heroin addiction60. Table 2 shows how treatment involving the use of heroin to treat heroin addiction has shown to be a better option than using methadone.

Table 3: A study in treatment with either heroin or methadone in regard to heroin

addiction;60

69% of users treated with heroin had a decrease in illicit drug use, while only 55% of users who were treated with methadone had a reduction in illicit drug use. 80% of heroin- treated patients had improved health, while only 74% of methadone-treated patients had improvements to their overall health60. This study used large sample sizes, with each sample involving over 350 patients. The issue with heroin assisted treatment, is that it has to be much more supervised than with methadone, with patients having to be monitored for at least 30 minutes after intravenous administration60. Typically, heroin use as a treatment is only considered to be an option for patients who are not successful with methadone treatment. In a study in Albuquerque, they treated heroin addicts with

40 methadone, and then followed up on the subjects 22 years later. They found that 41% of the subjects were still using heroin, while 23% of the people could not be found61.

Methadone is not a good treatment option because, as a full mu-opioid agonist, its use is very regulated (it is illegal in Russia)62. Buprenorphine, which is a partial mu-agonist, is still the preferable way to treat heroin addiction.

A type of treatment that is beginning to be studied is brain stimulation, where addiction can be treated without involving drugs. The four types of brain stimulation that are being studied include transcranial electric stimulation, transcranial magnetic stimulation, transcranial direct current stimulation, and deep brain stimulation63. Deep brain stimulation involves surgery, but it is shown to be the best way to work with the nucleus accumbens (Nacc), which is one of the main sections of the brain that deals with opioids. Transcranial electric stimulation involves sending an electric current across electrodes in the brain, and this can deal with the receptors that invoke withdrawal symptoms63. Transcranial magnetic stimulation has shown to be the least effective of the four methods because the magnetic pulse cannot reach deep into the brain. Transcranial direct current stimulation has shown to be effective at lowering craving for heroin, but it is not a consistent treatment. Deep brain stimulation’s surgical method shows the promise at being a non-drug treatment that will also be lasting at combatting addiction to heroin63.

There are other drugs used to treat withdrawal symptoms. Loperamide is used as an anti-diarrheal drug, but it has been shown to counter heroin withdrawal, as it also binds to the same opioid receptor as heroin, the mu-receptor. It is highly lipophilic, so it can easily permeate through the blood-brain barrier. The danger with loperamide is that it can be used to “get high.” It is dangerous to use this drug for a purpose other than anti-

41 diarrheal, as the traditional dose is 4-16mg/day, while a user will take around 200-400 mg/day when they are using it for the wrong reasons64. Using a drug in this large quantity for a purpose other than its intended use is an issue, and can lead to overdoses64.

Recently, there have been studies about natural or herbal treatments for heroin use or addiction. Most of these can be purchased over the counter, and they are mostly used to counter withdrawal effects. Kratom is a southeastern plant that is used to help with heroin addiction. The leaves have alkaloids similar to the ones in opioids, and it works with the same receptors that heroin involves65. The leaves can be chewed or mixed with other drinks, but this treatment is not regulated by the FDA. Clonidine is a FDA approved drug that is used to ADHD, but it is also being used by heroin addicts as it helps to manage withdrawals. Clonidine is a liquid, so there is a higher danger for an overdose, and in the case of an overdose, it should be treated with naloxone, which is the same treatment for a heroin overdose64. Kava is another herbal product that while it does not deal with any of the opioid receptors, it does work with dopamine, and uses a mechanism that helps withdrawal symptoms that come from too much dopamine being released64. These drugs all have overdose possibilities, so it is dangerous for one to go about using them without supervision. The best treatment plans for addiction remain to be a supervised treatment of buprenorphine or methadone.

User Demographics

The people who are the most at risk of becoming addicted to opioids are people who have some sort of mental disorder, whether it be depression, anxiety, schizophrenia, etc. According to Dr. Thomas Friedan, director of the Center of Disease Control,

42 “Patients with mental health or substance use disorders are at increased risk for nonmedical use and overdose from prescription opioids”66. From 2002 to 2012, the use of nonmedical opioids and heroin increased by 2,000 cases66. There has also been an increase in heroin users who are using some sort of non-medically prescribed opioid.

Combination of opioids is extremely dangerous, so it is a discouraging sign to see that the combination of heroin with other drugs is an increasing trend. Figure 12 shows the results of a study regarding the relationship between age and heroin use, and it shows that 18-25 year-olds are the most common heroin users. There is an alarming trend of 12-17 year- olds being the third most common group of users66.

Figure 12: A study in the relationship between age and heroin use; 18-25 years old most

common group;66

While younger individuals are using opioids, it is difficult for them to get treatment.

Right now, treatment options are mostly only available for older people who are chronic users. Figure 12 also shows that people who are older than 50 use heroin the least. The

43 number of heroin related emergency room visits has increased every year, with over

250,000 heroin related emergency room visits in 2011 alone. 18-34 year-olds are the demographic with the most emergency room visits due to opioid use in combination with other drugs. While 12-17 year-olds are the third most common demographic for heroin use, this generation does not typically combine their heroin with other drugs66.

Males, Caucasians, and American Indians are the three groups that are the most commonly linked to heroin use and abuse. As fentanyl began becoming commonly mixed into heroin and other drugs, minority groups have become more associated with opioid overdoses. African Americans and Hispanics have been increasingly more involved with opioid overdose67. Metropolitan areas have seen increased opioid overdose numbers.

From 2015-17, African Americans from the age 25-34 had a 108% increase in opioid related deaths, while Hispanics had an 81% increase67. Caucasians in the same age group and time frame showed a 42% increase in opioid overdose deaths. Synthetic opioid related deaths had even more increased usage across these demographics. From 2015-17,

Africans Americans aged 25-34 in metropolitan areas had a 287% increase in synthetic opioid related overdoses, while Hispanics had a 320% increase67. Caucasians had a 191% increase in synthetic opioid related overdoses during the same time frame67. These exponential increases in synthetic opioid related overdoses is concerning because new synthetic opioids, such as fentanyl analogs, continue to be created.

44 CONCLUSION

Heroin, fentanyl, carfentanil, hydrocodone, and krokadil are five of the opioids that are plaguing the United States. The extreme potency of each drug, in addition to the innovative ways people are using to acquire and distribute the drugs, make opioids a paramount issue. As pharmaceutical companies continue to develop novel synthetic opioids, the crisis will only worsen. It is difficult to regulate the drugs with any urgency when new ones continue to emerge. The arrival of krokadil in the United States is also concerning as it can be synthesized with household chemicals. With the pandemic pushing so many people into isolation over the last year and a half, it remains to be seen how much of an impact this will have on opioid usage. With the Dark Web providing such easy access to opioids, and the drugs being delivered to homes, it would not be suprising to see a drastic increase in opioid addiction in the next couple of years. Opioid use has already been exponentially increased, so the effect of the pandemic could make these numbers even more concerning. The only way the opioid epidemic will end is extremely diligent regulation of the drugs and better treatment options for addiction.

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